真性多血症

Pathogenesis and clinical features―recent progress in research：polycythemia vera

　JAK2遺伝子変異(V617F)は真性多血症，本態性血小板血症や原発性骨髄線維症に共通してがみられる．JAK2はエリスロポエチンなどのサイトカイン細胞内シグナル伝達の中心的役割を担うチロシンキナーゼで，V617F変異はキナーゼ活性を負に制御するJH2領域にアミノ酸置換があり，高いチロシンキナーゼ活性が持続し，血球増加をきたす．この変異は真性多血症のほぼ全例に認められ，最近ではJAK2エクソン12の変異も報告されている．いずれもSTAT5を含む様々なシグナル伝達分子の恒常的な活性化を認める．さらに，細胞内シグナルを負に制御するSOCS分子の発現異常も真性多血症の病態に関与している可能性がある．

JAK2 gene mutation(V617F)is commonly detected in polycythemia vera(PV), essential thrombocythemia and primary myelofibrosis. JAK2 is a non-receptor tyrosine kinase which plays an important role in intracellular signal transduction of cytokines including EPO, and it has four functional domains, JH1, JH2, SH2 and FERM. One of them, JH1 is a catalytic domain and negatively regulated by the JH2. Because V617F mutation is localized in the JH2 region, JH2 cannot suppress the JH1 kinase activity, resulting in constitutive activation of JAK2. Recently, it was also found that JAK2 exon 12 mutation was detected in a minority of PV patients. Several signaling molecules including STAT5 are constitutively activated in these JAK2 mutation-expressing cells. In addition, loss of function or down-regulation of SOCSs, negative regulators of cytokine signaling are also observed in PV patients. Taken together, these molecular events may be involved in the physiopathogenesis of PV.